1. Name Of The Medicinal Product
Ciprofloxacin 2 mg/ml Solution for Infusion
2. Qualitative And Quantitative Composition
1 ml solution for infusion contains: 2 mg ciprofloxacin (as ciprofloxacin lactate).
Excipients: 1 ml solution contains: 50 mg glucose monohydrate: equivalent to 45 mg glucose.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Solution for infusion
Clear, colourless or slightly yellow solution.
4. Clinical Particulars
4.1 Therapeutic Indications
Ciprofloxacin is indicated for the treatment of serious and/or life-threatening infections caused by ciprofloxacin-susceptible pathogens. The following indications can be considered for treatment with ciprofloxacin in adult patients when oral therapy is not possible or not reliable.
• complicated urinary tract infections,
• intra-abdominal infections (the anaerobic component should be covered by an appropriate antibacterial agent),
• complicated skin and soft tissue infections caused by gram-negative bacteria,
• osteomyelitis,
• sepsis caused by gram-negative bacteria,
• pneumonia caused by gram-negative bacteria. In case of Streptococcus pneumoniae infections, ciprofloxacin is not the substance of first choice.
In children and adolescents (5-17 years):
Acute pulmonary exacerbations of cystic fibrosis caused by Pseudomonas aeruginosa in children and adolescents aged from 5-17 years.
In case of mixed infections with anaerobes, ciprofloxacin must be combined with other antibiotics effective against anaerobes.
Consideration should be given to official guidance on the appropriate use of antibacterial agents.
4.2 Posology And Method Of Administration
The solution for infusion should be administered over an infusion period of 60 minutes.
Due to the increased risk of local reactions, higher intravenous doses in particular should only be administered via a large vein or a central line. Mixing with other solutions: see sections 6.2 and 6.6.
The duration of treatment depends upon the severity of infection, clinical response and bacteriological findings. Generally, acute and chronic infections (e.g. osteomyelitis), where the causative organism is known to be sensitive to ciprofloxacin, should be treated for at least three days after the signs and symptoms of the infection have disappeared.
Adults
The adult dosage is 200 - 400 mg ciprofloxacin twice daily.
In case of very serious, life-threatening or recurrent infections the dosage can be increased to 400 mg three times daily. The maximum daily dose is 1200 mg.
Osteomyelitis:
Prior to initiation of therapy, bacteriological sensitivity tests should be conducted. As with all other antibiotics, the patient should be monitored during therapy for the development of resistant strains of initially sensitive bacteria, especially P. aeruginosa and S. aureus (see the relevant statements in section 5.1). Average duration of treatment can be 4-6 weeks. If a prolonged treatment is necessary, a reassessment of treatment should be done at 2 months at the latest.
Children and adolescents
Dosage for aggravating pulmonary symptoms in children and adolescents with cystic fibrosis aged 5-17 years.
The intravenous dose is 10 mg/kg every 8th hour (maximum dose 1200 mg/day) (see section 4.4 and 5.2). The infusion time should be 60 minutes.
Sequential dosage can also be used: first 10 mg/kg intravenously at 8-hour intervals (maximum dose 1200 mg/day), followed by 20 mg/kg orally twice a day (maximum dose 1500 mg/day).
Recommended duration of treatment: 10-14 days.
There are no studies available on dosage in children with renal or hepatic insufficiency.
Ciprofloxacin is not indicated for other infections in this age group.
Special groups (adults)
Renal insufficiency:
|
|
|
|
|
|
|
|
Hepatic insufficiency:
Does not require alteration of dosage.
Renal and hepatic insufficiency:
Dosage as in renal insufficiency.
Elderly:
Elderly patients should receive a dose depending on the severity of the disorder and on creatinine clearance.
4.3 Contraindications
Ciprofloxacin is contraindicated in:
• patients with a hypersensitivity to ciprofloxacin, quinoline carboxylic acid derivatives or to any of the excipients
• pregnancy and lactation (see section 4.6)
• patients with a history of tendon disorder related to fluoroquinolone administration
• concurrent administration of ciprofloxacin and tizanidine
• children and adolescents - except for the treatment of acute pulmonary exacerbation of cystic fibrosis caused by Pseudomonas aeruginosa in children aged 5 to 17 years.
4.4 Special Warnings And Precautions For Use
Caution should be observed when prescribing the medicinal product to epileptic patients and persons with disorders in central nervous system function or cerebral circulation (e.g. tendency to spasms or previous seizure and vascular disorders in the brain, alterations in brain structure or stroke). These patients should be treated with ciprofloxacin only when the benefits outweigh the possible undesirable effects. These patients may experience adverse central nervous system effects due to ciprofloxacin use (see Section 4.8).
In single cases effects on the central nervous system appeared immediately after the first dose.
In isolated cases, depression and psychosis can cause self-destructive behaviour. In these cases, the use of ciprofloxacin should be discontinued and a doctor should be contacted immediately.
The use of ciprofloxacin may cause crystalluria. The hydration of the patient should be sufficient and care should be taken to avoid that the urine becomes too alkaline.
Fluoroquinolones may cause a haemolytic reaction in patients with glucose-6-phosphate dehydrogenase dysfunction.
Ciprofloxacin may aggravate symptoms of myasthenia gravis.
There is a risk of pseudomembranous colitis with broad-spectrum antibiotics possibly leading to a fatal outcome. It is important to consider this in patients suffering from severe, persistent diarrhoea. With ciprofloxacin, this effect has been reported rarely. If pseudomembranous colitis is suspected, treatment with ciprofloxacin should be stopped and appropriate treatment given. Drugs that inhibit peristalsis must not be given.
Ciprofloxacin has been found to cause arthropathy in the weight bearing joints of experimental animals at the growing stage. Analysis of the safety data on ciprofloxacin use in patients below 18 years of age, most of whom had cystic fibrosis, did not reveal any cartilage or joint damage due to the drug.
The clinical and pharmacokinetic data currently available supports the use of ciprofloxacin in the treatment of aggravating acute pulmonary symptoms during P. aeruginosa infection in children with cystic fibrosis. The use of ciprofloxacin for indications other than those related to cystic fibrosis is not, however, recommended, unless the expected benefit of treatment is likely to override the possible adverse reactions.
In isolated cases, hypersensitivity and allergic reactions have appeared immediately after the start dose, and in those cases, treatment should be stopped immediately.
Anaphylactic/anaphylactoid reactions could, in isolated cases, lead to a life-threatening shock, in some cases immediately after the start dose. In these cases, treatment must be discontinued and an appropriate treatment must be started (shock treatment).
The minimum Ciprofloxacin infusion time should be 30 min/200 mg and 60 min/400 mg. Local irritation at the puncture site has been reported during i.v. administration of ciprofloxacin, especially at infusion times of 30 min or shorter. The reaction manifests as local skin symptoms, which subside soon after the discontinuation of infusion. Local irritation can be minimized by using longer infusion times.
If any kind of tendon inflammation symptoms (e.g. painful swelling) occurs, the use of ciprofloxacin solution for infusion should be discontinued and the limb affected should not be exerted, should be made non-weight bearing and a doctor should be consulted.
Tendon rupture (mainly Achilles heel) has also been reported, mostly in elderly patients on systemic glucocorticoid therapy.
Ciprofloxacin has caused photosensitivity. During treatment with ciprofloxacin solution for infusion, the patient should avoid direct sunlight and UV-radiation. Treatment should be discontinued if light sensitivity appears (i.e. sunburn-like skin reaction).
Cardiac disorders: Since ciprofloxacin is associated with very rare cases of QT prolongation (see section 4.8), caution should be exercised when treating patients at risk for torsade de pointes arrhythmia.
Since ciprofloxacin has some activity against Mycobacterium tuberculosis, false-negative cultures may occur when the specimens are obtained during ciprofloxacin treatment.
Ciprofloxacin/CYP 1A2 substrates: Ciprofloxacin is an inhibitor of CYP 1A2. Therefore, caution should be exercised when concomitantly administering substances that are metabolised by this enzyme, since the risk of adverse reactions may be increased (see section 4.5).
This medicinal product contains 9 g glucose in 200 ml solution for infusion. This should be taken into account in patients with diabetes mellitus.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Theophylline
Simultaneous use of theophylline and Ciprofloxacin may increase plasma theophylline concentrations and enhance the adverse reactions due to that. If simultaneous use of these medicinal products cannot be avoided, the plasma theophylline concentration should be followed and theophylline dose cut if necessary.
CYP1A2 Enzymes
Ciprofloxacin inhibits CYP1A2 enzymes and may elevate the concentration of other substances in the serum (e.g. theophyllin, clozapine, tacrine, ropinirole, tizanidine), that are eliminated by this metabolic route. If these medicinal products are used concomitantly with ciprofloxacin, the patients should as a precaution, be monitored carefully for signs of adverse reactions. If required, the doses of these medicinal products should be reduced.
Other xanthine derivatives
On concurrent administration of ciprofloxacin and caffeine or pentoxifylline (oxpentifylline), raised serum concentrations of these xanthine derivatives were reported.
Phenytoin
Ciprofloxacin can increase or decrease the concentration of phenytoin that has been given concomitantly. It is recommended that phenytoin levels are monitored.
Mexiletine
Ciprofloxacin may reduce the clearance of mexiletine hydrochloride.
NSAIDs
Animal experiments have shown that simultaneous use of very high quinolone doses and some non-steroid anti-inflammatory agents (but not acetylsalicylic acid) may cause convulsions.
Ciclosporin
Transient rise of serum creatinine has been seen when ciprofloxacin has been used simultaneously with ciclosporin. The serum creatinine values of these patients should be checked regularly (twice a week).
Oral anticoagulants (e.g. warfarin)
Simultaneous use of ciprofloxacin with oral anticoagulant may enhance the potency of the anticoagulant.
Glibenclamide
Simultaneous use of ciprofloxacin and glibenclamide may enhance the potency of glibenclamide (hypoglycemia).
Probenecid
Probenecid reduces the renal clearance of ciprofloxacin. Simultaneous use of probenecid and ciprofloxacin may increase the plasma concentrations of ciprofloxacin.
Methotrexate
Simultaneous use of methotrexate with ciprofloxacin may prevent tubular transportation of methotrexate in the kidneys, which results is high plasma concentrations of methotrexate. This may increase the risk of toxic reaction due to methotrexate, and patients on methotrexate therapy must therefore be observed closely during simultaneous ciprofloxacin treatment.
Premedicants
It is recommended that opiate premedicants, (e.g. papaveretum) or opiate premedicants used with anticholinergic premedicants, (e.g. atropine or hyoscine) are not used concomitantly with ciprofloxacin, as the serum levels of ciprofloxacin are reduced. Co-administration of ciprofloxacin and benzodiazepine premedicants has been shown not to affect ciprofloxacin plasma levels. However, since decreased clearance of diazepam, with a prolonged half-life have been reported during co-administration of ciprofloxacin and diazepam, and in very rare cases with midazolam, careful monitoring of benzodiazepine therapy is recommended.
4.6 Pregnancy And Lactation
Pregnancy:
Ciprofloxacin must not be given during pregnancy. Clinical experience of use of ciprofloxacin in pregnant women is limited. In reproduction toxicity studies with quinolones, varying embryo/foetus-toxic effects have been observed. Quinolones have been found to be able to cause degeneration of articular cartilage in growing animals. However, this effect has not been reported as occurring during foetal development.
Lactation: Ciprofloxacin is contra-indicated during lactation since quinolones administered at therapeutic doses are excreted in the breast milk in quantities that can be expected to affect the infant.
4.7 Effects On Ability To Drive And Use Machines
Ciprofloxacin has minor or moderate influence on the ability to drive and use machines. This effect may be especially obvious in combination with alcohol use, when the dose is increased, when switching medication, or at the beginning of the treatment.When undesirable effects on the central nervous system, like dizziness, occur, it is prohibited to drive a vehicle or to operate machines.
4.8 Undesirable Effects
Adverse reactions have been reported in 5-14% of patients receiving ciprofloxacin. The most frequent adverse events involve the gastrointestinal tract and the central nervous system.
Adverse event frequencies have been categorized as follows:.
Very common (
The following adverse reactions have been reported during ciprofloxacin treatment:
Infections and infestations:
Uncommon: Candidiasis
Rare: Pseudomembranous colitis.
(See Section 4.4.)
Blood and lymphatic system disorders:
Common: Eosinophilia.
Uncommon: Leukopenia, granulocytopenia, anaemia, thrombocytopenia.
Very rare: Leukocytosis, thrombocytosis, agranulocytosis, haemolytic anaemia, pancytopenia and bone-marrow suppression. See Section on 'Investigations'.
Immune system disorders:
The following reactions occurred, in some cases, with the first dose of the medicinal product.
Rare: Hypersensitivity, anaphylactic/anaphylactoid reactions, dyspnoea, larynx oedema, drug induced fever.
Very rare: Shock (anaphylactic/anaphylactoid reactions progressing in very rare cases to life-threatening shock), angioedema. (See Section 4.4)
Metabolism and nutrition disorders:
Uncommon: Anorexia
Rare: Hyperglycaemia
Psychiatric and nervous system disorders:
Common: Dizziness, headache, agitation, tremor
Uncommon: Insomnia, confusion, dysgeusia
Rare: Hallucinations, paraesthesia, nightmares, depression, hypesthesia.
Very rare: Grand mal seizures (see section 4.4), clumsy gait, psychosis (see section 4.4), elevated intracranial pressure, ataxia, hyperesthesia, parosmia, migraine, syncope.
These reactions occurred, in some cases, with the first dose of the medicinal product.
If symptoms appear right after the initiation of treatment, the use of Ciprofloxacin should be discontinued and a doctor should be consulted.
In isolated cases, depression and psychosis can cause self-destructive behaviour. In these cases, the use of ciprofloxacin should be discontinued and a doctor should be contacted immediately.
Eye disorders:
Rare: Vision disorders (e.g. double vision, chromatopsia).
Ear and labyrinth disorders:
Very rare: Vertigo, tinnitus and transient impairment of hearing, particularly at high frequencies.
Cardiac disorders:
Uncommon: Tachycardia, palpitations.
Very rare: Ventricular arrhythmia, torsade de pointes*, QT prolongation*. These events were observed predominantly among patients with further risk factors for QTc prolongation (see section 4.4).
Vascular disorders:
Rare: Hypertension, hypotension.
Very rare: Hot flushes, peripheral oedema, fainting.
Respiratory, thoracic and mediastinal disorders
Uncommon: Pulmonary embolism, dyspnoea, pulmonary oedema, haemoptysis.
Gastrointestinal disorders:
Common: Nausea, diarrhea, vomiting, abdominal pain.
Uncommon: Indigestion, flatulence.
Rare: Pancreatitis.
Severe and prolonged diarrhea during or after antibiotic treatment may be a sign of a serious intestinal disease (pseudomembranous colitis) requiring immediate treatment. In these cases the use of Ciprofloxacin must be discontinued and the colitis must be treated with suitable medication. (See Section 4.4)
Drugs that slow down peristalsis are contraindicated.
Hepatobiliary disorders:
Rare: Hepatic necrosis, which may very rarely develop into lethal hepatic insufficiency.
Very rare: Hepatitis
Cases of cholestatic icterus, especially in patients with previous liver damage have been reported.
Skin and subcutaneous tissue disorders:
Common: Rash
Uncommon: Pruritus, urticaria.
Rare: Photosensitivity reaction, erythema nodosum, erythema multiforme (minor).
Very rare: Stevens Johnson syndrome, Lyell syndrome, petechia, blood blisters, papules, vasculitis, sweating.
Musculoskeletal and connective tissue disorders:
Uncommon: Joint pain and swelling, muscle pain.
Rare: Achilles tendonitis, generalized pain, pain in the limbs and back and chest.
Very rare: Aggravation of symptoms of myasthenia gravis, spasms, tenosynovitis.
Partial or complete Achilles tendon rupture has also been reported, mostly in elderly patients on systemic glucocorticoid therapy. (See Section 4.4)
If the patient develops symptoms of Achilles tendonitis (such as painful swelling), Ciprofloxacin must be discontinued and a doctor consulted.
Renal and urinary disorders:
Rare: Crystalluria, haematuria.
Very rare: Interstitial nephritis, transient disorders in renal function (including transient renal insufficiency).
General disorders and administration site conditions:
Common: Infusion site phlebitis. This may be prevented by using longer infusion times. Injection site irritation.
Symptoms of local irritation at the puncture site and local phlebitis have been reported after i.v. administration of ciprofloxacin, especially when infusion times of 30 minutes or less have been used (see Section 4.4)
Uncommon: Fatigue.
Rare: Weakness.
Investigations:
Common: Increased serum urea and creatinine, transient elevation of hepatic transaminases and alkaline phosphatase, especially in patients with previous liver damage.
Uncommon: Transient elevations of bilirubin levels, especially in patients with previous liver damage, changes in prothrombin values.
Very rare: Elevated amylase and lipase values.
4.9 Overdose
In acute cases of serious overdose, reversible renal toxicity has been reported in some cases. Further to common treatment methods, sufficient hydration should be given to avoid crystalluria. Kidney function (together with the pH of the urine) should be monitored. Hemodialysis or peritoneal dialysis only clears less than 10% of the ciprofloxacin dose from the body.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Fluoroquinolones; ATC code: J01MA02
Mode of action
Ciprofloxacin is a broad-spectrum antimicrobial drug of the quinolone group. The bactericidal effect of ciprofloxacin is based on blockade of bacterial DNA gyrase, which prevents bacterial metabolism. The effect applies to gram-negative and gram-positive bacteria at the mitotic or resting stage.
Ciprofloxacin has been found to have additive, and occasionally even synergistic effects with some beta-lactam antibiotics and aminoglycosides. Ciprofloxacin can also be used together with penicillins, cephalosporins, nitroimidazole derivatives (metronidazole) and aminoglycosides.
Mechanism of resistance
Resistance against ciprofloxacin develops slowly and gradually, usually via chromosomal mutation. Transferable plasmid-mediated quinolone resistance associated with qnr has been detected in quinolone-resistant clinical strains of E.coli and Klebsiella spp.
Due to its mechanism of action, ciprofloxacin does not generally show cross-resistance with penicillins, cephalosporins, aminoglycosides, tetracyclins, macrolide or peptide antibiotics, sulphonamides, trimethoprim or nitrofurane derivatives, although cross-resistance due to over-expression of multidrug effux systems has been described, particularly in Pseudomonas aeruginosa. Ciprofloxacin is also effective against bacteria that form beta-lactamase.
Cross-resistance has been seen within the quinolone group (gyrase inhibitors).
Cross-resistance between fluoroquinolones may occur when the mechanism of resistance is due to mutations in bacterial gyrases. However, single mutations may not result in clinical resistance, but multiple mutations generally do result in clinical resistance to all active substances within the class. Impermeability and/or active substance efflux pump mechanisms of resistance may have a variable effect on susceptibility to fluoroquinolones, which depends on the physicochemical properties of the various active substances within the class and the affinity of transport systems for each active substance.
Breakpoints
The EUCAST clinical MIC breakpoints (2004) are as follows:
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Susceptibility
The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.
Commonly susceptible species
Gram-negative aerobes
Citrobacter spp.
Citrobacter freundii
Enterobacter cloacae
Haemophilus influenzae
Moraxella catarrhalis
Morganella morganii
Proteus mirabilis
Proteus vulgaris
Serratia marcescens
Other pathogens
Legionella pneumophila
Species for which acquired resistance may be a problem
Gram-positive aerobes
Enterococci faecalis
Staphylococcus aureus*
Streptococcus spp.
Streptococcus agalactiae
Streptococcus pyogenes
Gram-negative aerobes
Acinetobacter spp.
Burkholderia cepacia
Providencia spp.
Enterobacter spp.
Escherichia coli
Klebsiella oxytoca
Klebsiella pneumoniae
Pseudomonas aeruginosa
Other pathogens
Mycoplasma pneumoniae
Inherently resistant organisms
Gram-positive aerobes
Enterococcus faecium
Gram-negative aerobes
Stenotrophomonas maltophilia
Other pathogens
Ureaplasma urealyticum
Anaerobes
Bacteroides fragilis
Clostridium difficile
* resistance rate> 50 % in one or more countries
MRSA are very likely to be resistant to ciprofloxacin and ciprofloxacin should not be used to treat presumed or known MRSA infections unless the organism is known to be susceptible.
5.2 Pharmacokinetic Properties
Absorption
Orally administered cirpofloxacin is absorbed quickly and almost completely, mainly from the small intestine: maximum plasma concentrations are reached within 1-2 hours of ingestion. Due to first-pass metabolism, bioavailability is 70-80 %. The peak plasma concentrations (Cmax) following doses of 250 mg and 500 mg have been 1.3 mg/l and 2.5 mg/l, respectively. Within the oral dosage range of 250-750 mg, the peak plasma concentrations and AUC values are directly proportional to the dose (the values increase as dosage increases).
When ciprofloxacin was administered as an i.v. infusion, the mean plasma peak concentrations were reached at the end of infusion. The pharmacokinetics of ciprofloxacin was linear within the dose range studied, i.e. up to an i.v. dose of 400 mg (infusion time 60 min).
Elimination half-life in serum after both oral and intravenous administration is 4-6 hours in patients with normal renal function. Total clearance after i.v. administration is about 35 h/l. No accumulation of ciprofloxacin or its metabolites was seen after daily administration of two or three i.v. doses.
Pharmacokinetic analyses showed that the AUCs were similar when ciprofloxacin was given as i.v. doses of 200 mg over 60 minutes at 12-hour intervals compared to oral doses of 250 mg at 12-hour intervals.
The AUCs were also similar when ciprofloxacin was given as 400 mg i.v. doses over 60 minutes at 12-hour intervals and as oral doses of 500 mg at 12-hour intervals. The peak plasma concentrations (Cmax) were equally high when i.v. doses of 400 mg were given over 60 minutes at 12-hour intervals or oral doses of 750 mg were given at 12-hour intervals. The AUCs were equal when ciprofloxacin was given as i.v. doses of 400 mg over 60 minutes at 8-hour intervals or as oral doses of 750 mg at 12-hour intervals.
Only 20-30 % of ciprofloxacin binds to plasma proteins, and it is mostly present in plasma in an unionised form. Due to this, ciprofloxacin is widely diffused in the extravascular space, and its concentrations in inflamed areas (e.g. tissues) are higher than in serum. Distribution volume in steady state is 2-3 l/kg.
Pharmacokinetics in children
In a clinical pharmaceutical trial where ten children aged 6-16 years were administered 10 mg/kg ciprofloxacin intravenously over 30 minutes at 12-hour intervals, the mean peak plasma concentration was 8.3 μg/ml and the corresponding minimum plasma concentration ranged within 0.09-0.26 μg/ml.
After the second i.v. dose, the patients began to take an oral dose of 15 mg/kg at 12-hour intervals, and this resulted in a mean peak concentration of 3.6 μg/ml after the first oral dose. Safety data on long-term use in children, including the effects of the drug on cartilage, are limited. (see Section 4.4)
Metabolism and excretion
Ciprofloxacin is mostly excreted unchanged through the kidneys into urine. After an oral dose, about 55% of ciprofloxacin is eliminated in urine, the corresponding percentage after a parenteral dose being approximately 70%. Renal clearance is 0.18-0.3 1/h/kg and total serum clearance is 0.48-0.60 1/h/kg. Renal excretion of ciprofloxacin takes place through both glomerular filtration and tubular secretion.
Only small amounts of ciprofloxacin are removed by haemodialysis or peritoneal dialysis.
The half-life of ciprofloxacin lies between 3 and 5 hours, both after oral and after intravenous administration.
Since ciprofloxacin is excreted not only via the kidneys, but also to a major extent via the gut, renal function must be substantially impaired before increases in serum elimination half-life of up to 12 hours are observed.
Ciprofloxacin undergoes some metabolism into desethylene ciprofloxacin (M1), sulphociprofloxacin (M2), oxociprofloxacin (M3) and formylciprofloxacin (M4). M1 and M3 have antimicrobial properties similar to or weaker than that of nalidixine acid.
The antimicrobial efficacy of M4, which is present in smaller quantities, corresponds to that of norfloxacin.
Pharmacokinetic studies on children with cystic fibrosis have shown that the recommended doses of 20 mg/kg twice a day orally or 10 mg/kg three times a day intravenously result in similar plasma concentration as a function of time as the currently recommended doses of adults
5.3 Preclinical Safety Data
Renal damage was observed in animal experiments only at high doses and in association with crystalluria. Renal damage without crystalluria was not seen in animal experiments and is not considered to be a primary toxic effect, but a typical secondary inflammatory foreign body reaction to the precipitation of a crystal-like complex of ciprofloxacin, magnesium and proteins.
Similar to other gyrase inhibitors, ciprofloxacin may induce damage to the large, bearing joints during the growth phase of juvenile animals.
Data on photomutagenicity/photocarcinogenicity show a weak photomutagenic or phototumorigenic effect of Ciprofloxacin in vitro and in animal experiments in comparison with other fluoroquinolones.
Ciprofloxacin showed positive results in two in vitro gene toxicity studies (mouse lymphoma cell forward mutation assay and rat hepatocyte DNA repair assay).
Other preclinical effects were observed only at exposures sufficiently in excess of the maximum human exposure that concern for human safety is negligible with regard to the animal data.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Glucose monohydrate
Lactic acid
Water for injection
Hydrochloric acid for pH adjustment
6.2 Incompatibilities
Ciprofloxacin is incompatible with injection solutions (e.g. penicillins, heparin solutions) which are chemically or physically unstable at its pH of 3.9 – 4.5. Unless compatibility is proven, the infusion should always be administered separately. For compatible co-infusion solutions see Section 6.6.
6.3 Shelf Life
100 mg/50 ml: 18 months
200 mg/100 ml: 24 months
400 mg/200 ml: 24 months
6.4 Special Precautions For Storage
Do not store above 25ºC.
Do not refrigerate or freeze.
Keep infusion bag within the sealed outer foil wrap before use, in order to protect from light and evaporation.
The infusion solution must be used immediately after opening.
6.5 Nature And Contents Of Container
Ciprofloxacin solution for infusion is supplied in transparent infusion bags (PVC or polyolefin) containing 50ml, 100ml or 200ml of sterile solution of ciprofloxacin 2 mg/ml. The bags are in an outer packaging of a double sheet of metallised polyethylenterephthalate.
Pack sizes:
5 x 50 ml, 10 x 50 ml, 50 x 50 ml
5 x 100 ml, 10 x 100 ml, 50 x 100 ml
5 x 200 ml, 10 x 200 ml, 20 x 200 ml
Not all pack sizes may be marketed.
6.6 Special Precautions For Disposal And Other Handling
The solution should be visually inspected for particulate matter and discoloration prior to administration. Only clear and colourless or slightly yellow solution should be used.
Keep infusion bag within the sealed outer foil wrap before use, in order to protect from light and evaporation.
For single use only.
Any unused solution and the bags should be adequately disposed of, in accordance with local requirements.
Ciprofloxacin solution for infusion should be administered without mixing with any other substances or infusion fluids. Ciprofloxacin infusion has been shown to be compatible with Ringer's solution, Sodium chloride 9 mg/ml (0.9%) solution for infusion, Glucose 50 mg/ml (5%) and 100 mg/ml (10%) solution for infusion and Fructose 100 mg/ml (10%) solution for infusion when infused in parallel. Unless compatibility is proven, the infusion solution should always be administered separately.
7. Marketing Authorisation Holder
Hospira UK Limited
Queensway
Royal Leamington Spa
Warwickshire
CV31 3RW
United Kingdom
8. Marketing Authorisation Number(S)
PL 04515/0208
9. Date Of First Authorisation/Renewal Of The Authorisation
8th May 2007
10. Date Of Revision Of The Text
January 2008 (V1404-6-9)
11 DOSIMETRY (IF APPLICABLE)
-
12 INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS (IF APPLICABLE)
-
No comments:
Post a Comment